Center for Translational Medicine, University of Maryland Baltimore, Maryland, USA.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Clin Transl Sci. 2018 Jul;11(4):435-443. doi: 10.1111/cts.12555. Epub 2018 Apr 27.
Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC of 69.3 ng/mL and ERK activity by 84% with an IC of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.
在急性髓细胞白血病（AML）患者中，连续给予批准剂量的索拉非尼不能长期耐受。本研究的目的是通过对 AML 患者的索拉非尼暴露-反应关系进行特征描述来优化给药方案。一个具有转运吸收室和肠肝再循环的单室模型描述了暴露情况。索拉非尼暴露与激酶靶点（FMS 样酪氨酸激酶 3（FLT3-ITD）和细胞外信号调节激酶（ERK））的靶向调节之间的关系通过抑制最大效应（E）模型来描述。索拉非尼可以以 69.3ng/mL 的 IC 抑制 FLT3-ITD 活性 100%，以 85.7ng/mL 的 IC 抑制 ERK 活性 84%（均针对代谢物效力进行了调整）。根据暴露-反应关系，模拟了不同频率下使用 200 或 400mg 的不同给药方案。模拟结果表明，与 400mg 每日两次（b.i.d.）相比，200mg 每日两次（b.i.d.）给药方案显示出相似的 FLT3-ITD 和 ERK 抑制活性，因此建议在 AML 患者的进一步临床试验中使用。
